Alkali supplementation as a therapeutic in chronic kidney disease: what mediates protection?

Abstract

Sodium bicarbonate (NaHCO₃) has been recognized as a possible therapy to target chronic kidney disease (CKD) progression. Several small clinical trials have demonstrated that supplementation with NaHCO₃ or other alkalizing agents slows renal functional decline in patients with CKD. While the benefits of NaHCO₃ treatment have been thought to result from restoring pH homeostasis, a number of studies have now indicated that NaHCO₃ or other alkalis may provide benefit regardless of the presence of metabolic acidosis. These data have raised questions as to how NaHCO₃ protects the kidneys. To date, the physiological mechanism(s) that mediates the reported protective effect of NaHCO₃ in CKD remain unclear. In this review, we first examine the evidence from clinical trials in support of a beneficial effect of NaHCO₃ and other alkali in slowing kidney disease progression and their relationship to acid-base status. Then, we discuss the physiological pathways that have been proposed to underlie these renoprotective effects and highlight strengths and weaknesses in the data supporting each pathway. Finally, we discuss how answering key questions regarding the physiological mechanism(s) mediating the beneficial actions of NaHCO₃ therapy in CKD is likely to be important in the design of future clinical trials. We conclude that basic research in animal models is likely to be critical in identifying the physiological mechanisms underlying the benefits of NaHCO₃ treatment in CKD. Gaining an understanding of these pathways may lead to the improved implementation of NaHCO₃ as a therapy in CKD and perhaps other disease states.

Keywords: bicarbonate; blood glucose; cholinergic anti-inflammatory pathway; clinical trial; complement; glomerular filtration rate; metabolic acidosis; pH.

Graphical abstract

Fig. 1.

Tubular casts in the kidney of Dahl salt-sensitive rats. Dahl salt-sensitive rats develop waxy proteinaceous casts (arrows) in renal tubules following high salt feeding. Two weeks of treatment with 0.1 M NaHCO₃ solution limits the formation of these tubular casts in the renal medulla (B) compared with 0.1 M NaCl solution (A). Images are shown at ×10 original magnification. Average cast areas in the renal cortex, outer medulla, and papilla in NaCl-treated (n = 9) and NaHCO₃-treated (n = 11) Dahl salt-sensitive rats fed a high-salt diet (8%) are shown in C. Data are expressed as means ± SE. Symbols represent individual animals. P_TREATMENT is the result of two-way ANOVA comparing kidney region and treatment. [The figure modified from Ray et al. (113).]

Fig. 2.

Proposed renoprotective mechanisms of alkali in chronic kidney disease (CKD). Several potential mechanisms have been proposed that underlie the beneficial effect of alkali supplementation in slowing the decline in glomerular filtration rate (GFR) and ultimately the progression of CKD. Solid lines represent established phenomena; dotted lines represent areas of ongoing research. Several of these mechanisms have been proposed to be mediated through renal compensatory responses to alkali, including 1) decreasing interstitial ammonium levels that lead to decreases in complement activation; 2) decreasing interstitial acidosis, which decreases local production of endothelin-1 (ET-1) and angiotensin II (ANG II); or 3) decreasing tubular H⁺ secretion, which can limit tubular cast formation. It is possible that other, extrarenal mechanisms also mediate a protective effect, either through 1) activation of the cholinergic anti-inflammatory pathway, which can decrease renal inflammation, or 2) correction of acidosis that can lead to enhanced blood glucose control.